Reabsorption of bile acids-from the intestine conserves lipoprotein cholesterol in the bloodstream. Conversely, blood cholesterol levels can be diminished by reducing reabsorption of bile acids.
One method of reducing the amount of bile acids that are reabsorbed and, thus, reducing serum cholesterol is the oral administration of compounds that sequester the bile acids and cannot themselves be absorbed. The sequestered bile acids consequently are excreted.
Compounds which have been suggested for bile acid sequestration include various ion exchange polymers. One such polymer is cholestyramine, a copolymer of divinylbenzene/styrene and trimethylammonium methylstyrene. It has been long recognized that this polymer is unpalatable, gritty, and constipating. More recently, various polymers have been suggested which are characterized by hydrophobic substituents and quaternary ammonium radicals substituted upon an amine polymer backbone (Ahlers, et al. U.S. Pat. Nos. 5,428,112 and 5,430,110 and McTaggert, et al., U.S. Pat. 5,462,730, which are incorporated herein by reference).
Thus, there is still a need to discover superior bile acid sequestrants.
The invention relates to the unexpected discovery that a new class of ion exchange resins have improved bile salt sequestration properties resulting in reduced dosages, which improve patient tolerance and compliance, thereby improving the palatability of the composition and are relatively easy to manufacture. The polymers, employed in the invention comprise non-absorbable, and optionally cross-linked polyamines as defined herein. The properties of the polymer which gave rise to the present invention were discovered during clinical trials of the polymer for its use in binding phosphate in patients suffering from hyperphosphatemia. The polyamines of the invention are characterized by one or more monomeric units of the formula: 
and salts thereof, where n is a positive integer and x is 0 or an integer between 1 and about 4. The polymer can be characterized by the substantial absence of one or more alkylated amine monomers and/or the substantial absence of one or more trialkylammonium alkyl groups. In preferred embodiments, the polymer is crosslinked by means of a multifunctional crosslinking agent.
The invention provides an effective treatment for removing bile salts from a patient (and thereby reducing the patient""s cholesterol level), particularly in patients with a serum LDL level of at least about 130 mg/dL. The invention also provides for the use of the polymers described herein for the manufacture of a.medicament for the treatment of hypercholesterolemia or for bile acid sequestration.
Other features and advantages will be apparent from the following description of the preferred embodiments thereof and from the claims.